The outpatient clinic provides a "well state" patient population for genetic and pharmacologic studies of persons with Unipolar (major depressive) and Bipolar (manic-depressive) disorders. Such a "well state" population is crucial in identifying biochemical, pharamcologic, or physiologic abnormalities which are present in persons vulnerable to affective disorder, and which may serve as genetic markers to affective illness. As a comparison group for such studies, we have developed a carefully screened panel of monozygotic and dizygotic twins without evidence of medical or psychiatric disorder. Continuing our collaboration with the Unit on Sleep Studies, we find clear evidence of greater sensitivity to induction of rapid eye movement (REM) sleep by a cholinergic agonist (Arecoline) in well state Bipolar patients off all medications, as compared with controls. Twin studies of genetic control of this response are underway. In other studies, alpha-adrenoceptors on platelets were found not to differentiate between patients and normal controls. Beta-adrenoceptors on lymphocytes did not show correlation between members of twin pairs, suggesting nongenetic sources of variation in receptor binding. A cell-culture bank of fibroblasts taken from Bipolar patients and normal controls has been developed. First results show no difference in Type A monoamine oxidase (MAO) activity between patients and normal controls.